The potential role of the MTHFR C677T polymorphism in the pathogenetic mechanisms of hormonal and metabolic response to antihyperglycemic therapy

Background. Type 2 diabetes mellitus (T2DM) is a multifactorial disease involving both environmental and genetic components. The methylenetetrahydrofolate reductase (MTHFR) gene, particularly the C677T polymorphism, influences folate metabolism and homocysteine levels and may affect metabolic processes and pharmacological response. Metformin is the first-line antihyperglycemic agent for T2DM, but interindividual variability in treatment response remains a key issue. The purpose of the work is to identify and assess the potential impact of a pathogenetically significant single-nucleotide polymorphism of the MTHFR gene on the development of obesity and type 2 diabetes mellitus in the implementation of the hormonal and metabolic effects of pharmacological factors. Materials and methods. This study included 28 patients with T2DM and metabolic syndrome (body mass index ≥ 30 kg/m2). Clinical, biochemical, and anthropometric parameters were assessed. Genotyping of the MTHFR C677T polymorphism was performed using polymerase chain reaction and restriction fragment length polymorphism. The effects of metformin therapy were evaluated by analyzing glycemic control, lipid profile, liver function, adipokine levels, and oxidative stress markers, taking into account the patients’ MTHFR genotypes. Results. Metformin use was associated with improved lipid profile in all genotypes. In addition, a genotype-specific reduction in liver enzyme activity was observed: aspartate aminotransferase levels decreased significantly in T allele carriers, while alanine aminotransferase reduced in patients with the CC genotype. These results suggest both pleiotropic and genotype-dependent hepatoprotective effects of metformin. No significant differences in MTHFR genotype distribution were found between metformin-treated and untreated groups. Conclusions. Metformin has beneficial metabolic effects in T2DM patients and may exert genotype-specific hepatoprotective properties. The C677T polymorphism of the MTHFR gene did not determine whether patients were prescribed metformin, but it may modulate liver-related biochemical respon­ses to the drug. These findings support the relevance of pharmacogenetic approaches to optimize therapy in T2DM.